EP4267110A1 - Formulation stable à libération prolongée de vitamine c et son procédé de préparation - Google Patents

Formulation stable à libération prolongée de vitamine c et son procédé de préparation

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Publication number
EP4267110A1
EP4267110A1 EP21909638.5A EP21909638A EP4267110A1 EP 4267110 A1 EP4267110 A1 EP 4267110A1 EP 21909638 A EP21909638 A EP 21909638A EP 4267110 A1 EP4267110 A1 EP 4267110A1
Authority
EP
European Patent Office
Prior art keywords
vitamin
formulation
prolonged release
release
stable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21909638.5A
Other languages
German (de)
English (en)
Inventor
Rajat Shah
Vishal Shah
Shajahan Abdul
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nutriventia Ltd
Original Assignee
Nutriventia Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nutriventia Ltd filed Critical Nutriventia Ltd
Publication of EP4267110A1 publication Critical patent/EP4267110A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/738—Rosa (rose)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to stable prolonged release vitamin C formulation and a process for preparation thereof. More specifically vitamin C formulation as described herein is free of any added stabilizer and it exhibits prolonged release of the active for more than 8 hours.
  • the formulation is comprised of about 10 to 20% by weight of at least one hydrophobic non -polymeric excipient and about 10 to 40% by weight of hydrophilic release controlling agent.
  • the invention also relates to the process for preparation of stable vitamin C formulation, wherein the active may be treated with hydrophobic release controlling agent at specific temperature conditions. The resulting molten mass is granulated with hydrophilic release controlling agent using process of aqueous granulation.
  • the granules may be mixed with suitable excipient and converted to compressible dosage forms, filled in the sachets or capsules or formulated in the form of jellies or gummies.
  • the formulation is stable and releases more than 85% of vitamin C over a period of 24 hours.
  • the process for preparation is simple, convenient and employs use of commonly used equipment, thus making it time and cost effective.
  • the formulation can be suitably orally administered to the subjects in need thereof, for maintaining significant concentration of vitamin C in blood plasma over prolonged time.
  • Vitamin C is a water soluble and thermolabile vitamin, being an essential nutrient for human life. It is known to play an important role as antioxidant due to its presence in the body fluids. It causes an increase in the rate of absorption of iron, calcium and folic acid and hence reduces allergic reactions, boosts the immune system, stimulates the formation of bile in the gall bladder and facilitates the excretion of various steroids. In the body vitamin C plays an essential role in the production of collagen tissue around bones, teeth, cartilage, skin, and damaged tissue.
  • Vitamin C is highly soluble in water and alcohol and is easily oxidised to dehydroascorbic acid in its solubilised form. The rapid degradation in aqueous media is still a major factor in the formulation of its products. It is also reported that its oxidation occurs rapidly in an alkaline environment especially at higher temperatures (>50°C) and its reaction with oxygen is strongly catalysed by metal ions, particularly cupric and ferric ions.
  • the degradation proceeds both by aerobic and anaerobic pathways and depends upon many factors such as oxygen, temperature, light, pH and storage conditions.
  • different strategies have been employed in the industry. These include the use of stabilizers such as citric acid, vegetable oil, antioxidants, synergists, emulsifiers and the like.
  • stabilizers such as citric acid, vegetable oil, antioxidants, synergists, emulsifiers and the like.
  • the techniques of entrapment of vitamin C in multiple emulsions and encapsulation in nanosuspension have shown significant improvement in the stabilization.
  • the control of medium pH, polarity and viscosity also prolong the shelf life of vitamin C.
  • Vitamin C is a substance of extreme importance to the body, this vitamin is not synthesized by humans. Therefore, to meet daily needs, it is necessary to eat foods rich in vitamin C or intake of medicines containing ascorbic acid as an active ingredient. To maintain saturation level of this substance in the body, the recommended daily dose of ascorbic acid varies from several mg up to 1-2 g, according to the nutritional scientists. However, ascorbic acid in aqueous media undergoes rapid oxidation under natural light, thermal and alkaline conditions, resulting in its decomposition and the loss of its biological activity. Therefore, the search for stable dosage forms that can release ascorbic acid for an extended period and in controlled manner is of paramount importance.
  • Controlled or sustained release drug formulations became very popular in the last two decades, since they overcome some of the disadvantages of conventional solid dosage forms such as fluctuations of the drug concentration in the plasma and on the site of action, frequency of dosing, drug toxicity and costs.
  • controlled release dosage forms are designed to provide continuous supply of small but therapeutic amounts of active compound at rates sufficiently controlled to maintain therapeutic plasma concentration levels and prolong therapeutic action over desired time span.
  • IN patent application 201301108 discloses oral modified release composition as a dietary supplement which comprises of pulverized ascorbic acid, vegetable oil and non-swelling release retardant like wax or fatty acid. Tocopherol and citric acid are used as stabilizers in the formulation. The combination of oil and non-swelling release retardant provides modified release of ascorbic acid from the formulation.
  • CN patent application 1582922 discloses a vitamin C sustained-release pill composition
  • a vitamin C sustained-release pill composition comprising core of vitamin C, antioxidant, anti-oxidation synergistic agent and the pill is coated with slow-release coating material, plasticizer, pore-forming agent and antifoaming agent.
  • EP patent application 1942875 discloses a controlled release formulation comprising active agent, e.g. Acerola vitamin C, along with non-polymeric release retardant combined with pH independent non-swelling release retardant (e.g. polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon® SR), Polymethacrylic acid derivatives.
  • active agent e.g. Acerola vitamin C
  • non-polymeric release retardant e.g. polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon® SR), Polymethacrylic acid derivatives.
  • JP patent application 06647902 discloses a sustained release oral granule composition comprising ascorbic palmitate in the matrix system of HPMC and poly glyceryl fatty acid ester.
  • US patent 8920837 relates to the combination of non-swelling pH dependent and non-swelling pH independent release retardant for ascorbic acid formulation.
  • KR patent application 1826994 covers vitamin C tablet formulation with controlled release property, comprising HPMC of various viscosity grades in combination, along with other excipients such as diluent, binder and lubricant.
  • US 20150141503 relates to solid, colour-stable L-ascorbic acid compositions, which are in the form of a powder or granule. These improved compositions have a high amount of vitamin C and they have excellent colour stability.
  • the formulation comprises a specific lubricant and suitable binder, which enhances the colour-stability (especially when used in a tablet).
  • Prior art literature demonstrates variety of approaches for controlling the release of active from the formulation, such as use of pH dependent and pH independent polymers or fatty excipients in combination with coating excipients.
  • the release of active from these formulations is not consistent and many of these exhibit dose dumping, thus affecting the overall performance of the formulation.
  • none of these formulations address stability aspect or improved shelf life of the formulations; or they make use of speciality excipient from the category of stabilizers to achieve stability, thus adding to the cost of the product.
  • the researchers of the present invention have surprisingly found that optimum selection of combination of hydrophobic non -polymeric excipient and the hydrophilic release controlling agent has resulted in stable formulation which exhibits prolonged release of vitamin C over a period of more than 8 hours.
  • the formulation is stable, even though it is free of any added stabilizer and prepared by exposing the active to moderate conditions of heat followed by aqueous granulation.
  • the formulation is granular in nature, which can be compressed in suitable dosage forms, filled in capsules or sachets, or formulated in the form of jellies and gummies for convenient administration to the subjects for maintaining significant concentration of vitamin C in body over 24 hours.
  • the invention also relates to the process for preparation of stable prolonged release vitamin C formulation, wherein vitamin C may be treated with at least one hydrophobic non-polymeric excipient and the resulting mass may be granulated using at least one hydrophilic release controlling agent by the process of aqueous granulation to get free flowing granules.
  • the granules may be mixed with at least one excipient, which is acceptable in nutraceutical and food industry, for converting into suitable dosage form for oral administration.
  • the formulation is free of any added stabilizer, but it exhibits stability over a period of proposed shelf life of the product, when stored at standard conditions of temperature and humidity.
  • the formulation, as described herein also exhibits continuous release of more than 85% of vitamin C throughout the day, which helps to maintain significant concentration of the detectable amount of active in the body for prolonged time.
  • None of the prior art references describe a stabilizer free granular formulation of vitamin C, which is stable, even though prepared by exposing the active to moderately high temperature conditions as well as aqueous granulation process.
  • the formulation is comprised of combination of hydrophobic non-polymeric excipient and hydrophilic release controlling agent. The process of treating vitamin C at specific temperature condition with hydrophobic non-polymeric excipient, and then subjecting it to aqueous granulation using hydrophilic release controlling agent, results into a stable vitamin C formulation with prolonged release of active over desired time.
  • Main objective of the invention is to provide stable and prolonged release vitamin C formulation and the process for preparation of said formulation.
  • Another objective of the invention is to provide stable vitamin C formulation, which is free of any added stabilizer.
  • vitamin C formulation which exhibits prolonged release of more than 85% of the active throughout the day, for more than 8 hours.
  • vitamin C formulation which exhibits prolonged release of more than 85% of the active, thus resulting into significant concentration of the active in the blood plasma over 24 hours.
  • Another objective of the invention is to provide stable vitamin C formulation which is comprised of combination of hydrophobic non-polymeric excipient and hydrophilic release controlling agent.
  • Another objective of the invention is to provide stable formulation comprising about 40 to 75% by weight of vitamin C in combination with about 10 to 20% by weight of hydrophobic non-polymeric excipient and about 10 to 40% by weight of hydrophilic release controlling agent.
  • Important objective of the invention is to provide stable vitamin C formulation comprising at least one hydrophobic non-polymeric excipient selected from the group of, but not limited to fatty acids, long chain alcohols, fats, lipids, waxes, oils and the combination thereof.
  • the objective of the invention is also to provide stable vitamin C formulation comprising at least one hydrophilic release controlling agent, selected from the group of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, polyacrylic acid polymers and copolymers, carboxymethylcellulose (CMC), sodium CMC, potassium CMC, calcium CMC, methylcellulose, hydroxyethyl cellulose (HEC), vinyl pyrrolidonevinyl acetate copolymer, polyvinyl alcohol, starch, carbomer, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof.
  • hydrophilic release controlling agent selected from the group of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, polyacrylic acid polymers and copolymers, carboxymethylcellulose (CMC), sodium CMC, potassium C
  • One important objective of the invention is to provide a process for preparation of stable vitamin C formulation, wherein the active may be treated with about 10 to 20% by weight of hydrophobic non-polymeric excipient at specific temperature conditions.
  • the resulting mass is granulated with about 10 to 40% by weight of hydrophilic release controlling agent using process of aqueous granulation.
  • Another objective of the invention is to provide stable vitamin C formulation in the form of granules, wherein the granules may be mixed with about 0.5 to 10% by weight of suitable excipients, acceptable in nutraceutical and food industry and converted into final dosage forms like tablets and capsules.
  • One more objective of the present invention is to provide stable vitamin C formulation, which may further be comprised of one or more bioactives selected from the group of citrus bioflavonoids, zinc citrate, rose hip extract, vitamin D, vitamin B complex, vitamin E, trace minerals, ginger extract, Echinacea extract, turmeric extract, probiotics, essential amino acids and the combination thereof.
  • bioactives selected from the group of citrus bioflavonoids, zinc citrate, rose hip extract, vitamin D, vitamin B complex, vitamin E, trace minerals, ginger extract, Echinacea extract, turmeric extract, probiotics, essential amino acids and the combination thereof.
  • the objective of the invention is to provide process for preparation of prolonged release stable vitamin C formulation, which is simple, convenient and employs use of commonly used equipment, thus making it time and cost effective.
  • the formulation can be suitably orally administered to the subjects in need thereof, for maintaining significant concentration of detectable amount of vitamin C in the blood plasma over 8 hours to 24 hours.
  • the invention relates to stable prolonged release vitamin C formulation, which is free of any added stabilizer.
  • the formulation may be comprised of at least one hydrophobic non-polymeric excipient and hydrophilic release controlling agent along with one more excipient which is acceptable in nutraceutical and pharmaceutical industry.
  • the invention also relates to the process for preparation, wherein the active may be treated with hydrophobic non-polymeric excipient at specific temperature condition, followed by aqueous granulation with hydrophilic release controlling agent to get the granular formulation.
  • the granules are stable, even though prepared by exposure to conditions like moderate heat and the aqueous granulation process.
  • the stable granules may be mixed with suitable excipient and converted into compressible dosage forms, filled in sachets, capsules or formulated in jellies and gummies.
  • the formulation as described herein employs vitamin C (also commonly and synonymously called as ascorbic acid and ascorbate interchangeably) which is in the form of white or almost white crystalline powder or colourless and odourless crystal. It may also exist in the form of sodium ascorbate which is white and odourless solid. It is highly unstable in nature and exhibits discoloration or darkening of white shade, upon exposure to air and moisture. It is freely soluble in water and sparingly soluble in ethanol. Vitamin C undergoes degradation after melting at higher temperature such as 190°C. The active may be obtained from natural source or it may be a synthetic product. As vitamin C is sensitive to heat, air and moisture, it is critical to formulate stable formulations of vitamin C in various dosage forms for oral administration.
  • the formulation may be comprised of about 30 to 85% by weight of vitamin C. More preferably it may be comprised of about 40 to 75% by weight of vitamin C.
  • vitamin C formulation of the present invention is free of any specific added stabilizer and also avoids addition of overages, thus reducing the cost of production.
  • hydrophobic non-polymeric excipient relates to the formulation component which is used for treating vitamin C at specific temperature condition. This component is found to be explicitly responsible for stabilization of the active, and therefore no other stabilizer is required to be added in the formulation. These carriers are insoluble in water and therefore highly hydrophobic in nature.
  • the hydrophobic non-polymeric excipient may be preferably obtained from natural source, although the carriers may be available from synthetic and semi-synthetic sources.
  • Treatment of vitamin C with hydrophobic non-polymeric excipient at specific temperature condition results into protection of the active from undergoing degradation while exposing to aqueous environment during granulation phase, followed by hot air during drying. Vitamin C stabilized by treatment with hydrophobic non-polymeric excipient imparts hydrophobicity to the active, which may retard the release of the active from the formulation.
  • hydrophobic non-polymeric excipient may be selected from the class of, but not limited to lipids, fats, waxes and the combination thereof.
  • the excipient may also be selected from, but not limited to, beeswax, candelilla wax, carnauba wax, spermaceti, paraffin wax, synthetic waxes and the combination thereof.
  • the hydrophobic non-polymeric excipient may be selected from, but not limited to, saturated fatty acids having 12 to 28 carbons, such as stearic acid, fatty alcohols having from 16 to 44 carbons, cetyl alcohol, pegylated fatty acids, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, derivatives of mono-diglycerides, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, pegylated vegetable oils, partially hydrogenated oils of soy, cottonseed, palm, sunflower, castor oil, sorbitan esters, polyoxyethylene sorbitan esters, propylene glycol mono-or diesters, phospholipids, phosphatides, cerebrosides, gangliosides, cephalins, lipids, glycolipids, sulfatides, sugar esters, sugar ethers, sucrose esters, sterols, polyg
  • the formulation as described herein may comprise of about 5 to 30% by weight of hydrophobic non-polymeric excipient. More preferably it may be comprised of about 10 to 20% by weight of this excipient.
  • hydrophilic release controlling agent may relate to the formulation component of vitamin C prolonged release formulation, which is hydrophilic and swellable and/or erodible in nature. This is a component which is explicitly responsible for controlling release of vitamin C from the formulation. As described herein, it is used for preparation of granules of vitamin C, which can be conveniently formulated in compressible dosage forms or can be filled in the capsules. Hydrophilic release controlling agent aids to improve compression process by avoiding the problems like picking and sticking, which have been observed during compression of vitamin C granules containing only hydrophobic non-polymeric excipient as release controlling agent.
  • the hydrophilic release controlling agent may be selected from the group of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, carboxymethylcellulose (CMC), sodium CMC, potassium CMC, calcium CMC, methylcellulose, hydroxyethyl cellulose (HEC), polyacrylic acid polymers and copolymers, vinyl pyrrolidone-vinyl acetate copolymer, polyethylene oxide, polyvinyl alcohol, starch, starch derivatives, modified starch, carbomer, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof.
  • HPMC hydroxypropylmethyl cellulose
  • HPC hydroxypropyl cellulose
  • CMC carboxymethylcellulose
  • HEC hydroxyethyl cellulose
  • polyacrylic acid polymers and copolymers vinyl pyrrolidone-vinyl acetate copolymer
  • the formulation may be comprised of one hydrophilic release controlling agent or the combination thereof, to achieve prolonged release formulation of the active.
  • the formulation may be comprised of about 5 to 50% by weight of hydrophilic release controlling agent, more preferably 10 to 40% of the release controlling agent.
  • sustained release refers to release pattern of the active from the formulation, at desired rate throughout the day over 24 hours.
  • the formulation, as described herein, is designed in such a way that more than 85% of vitamin C is released for a period of more than 8 hours in a day.
  • specific amount of the active would be released in the body system at definite time intervals for maintaining significant concentration of the active in blood plasma over prolonged time.
  • prolonged release composition may be comprised of at least one excipient, which is acceptable in nutraceutical, pharmaceutical and cosmetic industry.
  • the excipient may help as a processing aid in formulating the granules in desired dosage form intended for oral administration.
  • Prolonged release composition of vitamin C as described herein may be comprised of about 0.5 to 10% by weight of at least one excipient, which is selected from natural, semi-synthetic or synthetic sources.
  • the formulation may be comprised of diluents known in the art, but not limited to microcrystalline cellulose, silicified microcrystalline, powdered cellulose, microfine cellulose, corn starch, rice bran extract, mannitol, maltodextrin, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, or mixtures thereof.
  • the diluents may also be selected from glucose, lactose, sucrose, dextrose, fructose, compressible sugar, or mixtures thereof.
  • the binders may be selected from the group of low viscosity cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, carboxymethylcellulose (CMC), sodium CMC, potassium CMC, calcium CMC, methylcellulose, hydroxy ethyl cellulose (HEC), microcrystalline cellulose; polyvinylpyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, starch, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof.
  • HPMC hydroxypropylmethyl cellulose
  • HPC hydroxypropyl cellulose
  • CMC carboxymethylcellulose
  • HEC sodium CMC
  • potassium CMC calcium CMC
  • methylcellulose hydroxy ethyl cellulose
  • microcrystalline cellulose polyvinylpyrrolidone (PVP), vinyl pyrrolidon
  • the lubricants may be selected from magnesium stearate, calcium stearate, sodium benzoate, talc, or mixtures thereof.
  • the glidants may be selected from suitable glidants known in the art and commonly used in the industry, selected from the group of stearate, starch, talc and the derivatives.
  • a formulation in the form of prolonged release vitamin C comprising
  • hydrophilic release controlling agent selected from the group of cellulose and cellulose derivatives; vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, starch, starch derivatives, modified starch, carbomer, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof, and
  • excipient selected from the group of fillers, diluents, disintegrants, lubricants, binders, glidants, anti-caking agents, surfactants, channelizing agents, vehicles, buffers, complexing agents, gum bases, viscosity enhancers and the combination thereof.
  • the formulation as described herein may also be further comprised of other bioactives such as bioflavonoids, zinc citrate, rose hip extract, vitamin D, B complex and vitamin E, trace minerals, ginger extract, Echinachea extract, turmeric extract, probiotics, essential amino acids and the combination thereof., in combination with vitamin C.
  • bioactives such as bioflavonoids, zinc citrate, rose hip extract, vitamin D, B complex and vitamin E, trace minerals, ginger extract, Echinachea extract, turmeric extract, probiotics, essential amino acids and the combination thereof.
  • formulations which can be used as such or in suitable dosage forms, such as compressible dosage forms, capsules, jellies or gummies, may exhibit improved stability when exposed to stress conditions for example at high moisture and/or high temperature conditions.
  • the formulation as described herein provides reliable, reproducible and consistent prolonged release of vitamin C throughout the day.
  • the formulation is designed in such a way that it will exhibit prolonged release of vitamin C for more than 8 hours in a day in vitro, thus resulting in maintenance of significant concentration of vitamin C in blood plasma over a period of 8 to 24 hours.
  • the process for preparation of vitamin C formulation employs commonly available and easy to use industrial equipment.
  • the process for preparation of the prolonged release formulation may be comprised of treatment of vitamin C with hydrophobic non-polymeric excipient at specific temperature conditions, using suitable equipment, by the way of melt granulation, melt extrusion, melt solidification and the combination thereof. Suitable parameters of temperature, revolutions and torque may be selected for carrying out melt granulation.
  • the process may be carried out by varying the temperature in the range of 40 to 120°C.
  • the molten form can be further processed to get granules suitable for compression into tablet dosage form.
  • the molten mass may be subjected to aqueous granulation using hydrophilic release controlling agent through process such as fluidized-bed granulation, high-shear granulation, extrusion, or other suitable wet granulation processes.
  • aqueous granulation process results into uniform and smooth granules, which can be conveniently converted and or compressed in desired dosage form, without any problems of picking or sticking to the equipment.
  • the process for preparation is easy, economic and also makes use of commonly available industrial equipment.
  • the granules may be formulated in compressible dosage forms, or filled in sachets or capsules using at least one excipient, which is acceptable and commonly used in industry.
  • the molten mass obtained after treatment of vitamin C with hydrophobic non-polymeric excipient is subjected to stability studies at various temperature and humidity conditions.
  • the granules obtained at this stage are hydrophobic and these may be difficult for subjecting to compression because of picking and sticking problems.
  • the granules are further subjected to aqueous granulation using hydrophilic release controlling agent, which make it suitable for converting into suitable compressible dosage forms.
  • the prolonged release formulation as described herein, is subjected to stability study as well as dissolution study to understand release profile of active over extended time period.
  • the formulation is also subjected to evaluation of pharmacokinetic profile in healthy human volunteers to study plasma profile of the active after oral administration in comparison to placebo formulation.
  • the pharmacokinetic evaluation confirmed the prolonged release characteristics of vitamin C formulation over 8 to 24 hours.
  • the data also indicates that the formulation exhibited superiority over the placebo by providing significant blood plasma concentration of Vitamin C for prolonged period over 24 hours.
  • Table 1 Composition of vitamin C prolonged release tablet (Formulation 1)
  • Vitamin C Ascorbic acid
  • carnauba wax and stearic acid was blended well.
  • the blended dry mix was processed in hot melt extruder at heating temperature 60°- 90°C.
  • the resultant mass was milled and passed through mention 30 mesh suitable mesh.
  • the treated mass was granulated with hydroxypropyl methyl cellulose in the ribbon mixer granulator with purified water.
  • the wet granules were dried and sized.
  • the sized granules were lubricated with colloidal silicon dioxide and magnesium stearate.
  • the lubricated granules were compressed into tablets.
  • Table 2 Composition of vitamin C prolonged release tablet (Formulation 2) Process:
  • Vitamin C was mixed with stearic acid and blended well.
  • the blended dry mix was processed in hot melt extruder at heating temperature 60°-90°C.
  • the resultant molten mass was milled and passed through 30 mesh.
  • the treated mass was granulated with hydroxypropyl methyl cellulose in the ribbon mixer granulator with purified water.
  • the wet granules were dried and sized.
  • the sized granules were lubricated with colloidal silicon dioxide and magnesium stearate.
  • the lubricated granules were compressed into tablets using 18 x 9 mm punches to get the tablets having sufficient hardness with 5.5 mm thickness.
  • the dissolution of the compressed tablet formulation was carried out in 900ml citrate buffer of pH 3.0 using paddle at lOOrpm.
  • Vitamin C released during dissolution study was estimated using HPLC method, using pH 3 buffer and Acetonitrile in a ratio of 3:2 as mobile phase and standard column run conditions.
  • the injection volume was 10 mL and the detection was carried out at 244nm.
  • Formulation 1 and 2 exhibits prolonged release of vitamin C without initial dose dumping and maintains the drug release over a period of more than 8 hours.
  • Table 4 Composition of vitamin C prolonged release tablet (Formulation 3)
  • Table 5 Composition of vitamin C prolonged release tablet (Formulation 4)
  • Formulation 3 and 4 exhibits prolonged release of vitamin C without initial dose dumping and maintains the drug release for more than 8 hours.
  • Example 5 Stability study of prolonged release Vitamin C prototype formulations The following prototype formulation trials were carried out using various combinations of hydrophobic non-polymeric excipient and/or hydrophilic release controlling agent. These trial formulations were subjected to 40°C/75% RH for one month to study stability aspects of the formulation and role of formulation components on the stability.
  • Ascorbic acid, carnauba wax/stearic acid were dispensed and sifted.
  • the mixture was blended well.
  • the blended dry mix is passed through HME operating with the heating temperature 60°-90°C.
  • the resultant mass was milled and passed through suitable mesh, preferably mesh 30.
  • the mass was granulated with HPMC with purified water (Formula 3 and 5).
  • the wet granules were dried and sized.
  • the granules were subjected to stability study using specific conditions of temperature and relative humidity, 40°C/75% RH for one month.
  • the assay of granules was checked before and after the stability study.
  • Vitamin C, carnauba wax or stearic acid were sifted and the sifted material is blended well.
  • the blended dry mix is passed through HME operating with the heating temperature 60°-90°C.
  • the resultant mass was milled and passed through suitable mesh.
  • the treated granules were granulated with hydroxypropyl methyl cellulose with purified water (Formula 7, 9 and 10).
  • the wet granules were dried and sized.
  • the sized granules were lubricated with colloidal silicon dioxide and magnesium stearate OR with calcium silicate.
  • the lubricated granules were compressed into tablets by using 18mm x 9mm punches.
  • Vitamin C was mixed with carnauba wax/stearic acid/cetyl alcohol/glyceryl monostearate and the mixture was blended well.
  • the blended dry mix was processed in hot melt extruder at heating temperature 60°-90°C.
  • the resultant mass was milled and passed through suitable mesh.
  • the treated granules were milled and passed through sieve.
  • the sized granules were lubricated with colloidal silicon dioxide and magnesium stearate or with calcium silicate.
  • the wet granules were dried and sized.
  • the lubricated granules were compressed into tablets by using 18 mm x 9mm punches.
  • Vitamin C formulation and their respective dissolution profile are mentioned below.
  • Vitamin C was mixed with carnauba wax/stearic acid/cetyl alcohol/gly ceryl monostearate and the mixture was blended well.
  • the blended dry mix was processed in hot melt extruder at heating temperature 60°-90°C.
  • the resultant mass was milled and passed through mesh size 30.
  • the treated granules were milled and passed through sieve.
  • the sized granules were lubricated with colloidal silicon dioxide and magnesium stearate or with calcium silicate.
  • the resultant mass was milled and passed through suitable mesh.
  • the treated mass was granulated with hydroxypropyl methyl cellulose with purified water.
  • the wet granules were dried and sized.
  • the lubricated granules were compressed into tablets.
  • Vitamin C formulation and their respective dissolution profile are mentioned below.
  • Example 9 A Composition of prolonged release vitamin C Formulation comprising bioactives
  • Vitamin C Formulation Ascorbic acid, carnauba wax or stearic acid are sifted and the material is blended well.
  • the blended dry mix is passed through hot melt extruder operating with the heating temperature 60°-90°C.
  • the resultant molten mass is milled and passed through the mesh.
  • the treated granules are granulated with hydroxypropyl methyl cellulose with purified water.
  • the wet granules are dried and sized.
  • the granules are mixed well with citrus bioflavonoids, Rose hip extract or zinc citrate (Formula 15 or 16 respectively).
  • the sized granules are lubricated with colloidal silicon dioxide and magnesium stearate or with calcium silicate.
  • the lubricated granules are compressed into tablets by using 18mm x 9mm punches for 500 mg strength tablet and using 21.5x11.5 punches for 1000 mg strength.
  • Table 16 Stability studies of Bulk granules packed in HDPE drums.
  • the prolonged release Vitamin C formulation of the invention was found to be stable at two different conditions of temperature and humidity, when stored for 3 months.
  • the formulation also exhibits prolonged release of vitamin C, at initial time point and at the end of stability study.
  • the formulation, as described herein comprised of hydrophobic non-polymeric excipient is stable and exhibits prolonged release of more than 85% of active over a period of more than 8 hours, without any dose dumping.
  • the granules treated with hydrophilic release controlling agent can be conveniently compressed in tablet dosage forms, without any capping and sticking problem.
  • a double-blind, balanced, randomized, single dose, parallel arm, placebo controlled study was conducted to evaluate the pharmacokinetics of Vitamin C Prolonged Release formulation (called as test product or test formulation) in healthy, adult human subjects under fasting conditions. Another purpose of the study was to monitor the safety and tolerability of a single dose of the test formulation. A total of 18 subjects were allocated for specific treatments as per the randomization schedule (9 subjects in each group). During the study, subjects were fasted for at least 10 hours and administered a single dose of either test product or placebo tablet (look alike of test product, excluding active-vitamin C) as per the randomization.
  • Blood samples were withdrawn from all 18 subjects at different intervals for characterization of single dose pharmacokinetics of the test formulation.
  • the blood samples were analysed for plasma Vitamin C concentration.
  • Vitamin C prolonged release tablets The pharmacokinetic evaluation of Vitamin C prolonged release tablets indicates that significant concentration of vitamin C in plasma was found for extended period of time and that confirms the prolonged release characteristics of the test product over 8 to 24 hours. The data also indicates that test formulation showed superiority over the placebo by providing significantly higher plasma concentration of Vitamin C in plasma for prolonged period over 24 hours. The study also concludes that Vitamin C prolonged release formulation, as described herein is well tolerated and safe for administration to the subjects in need thereof.
  • Vitamin C formulation of the present invention exhibits more than 80% release of the active over 8 hours, as shown through in-vitro dissolution studies and the formulation also produces significant concentration of detectable levels of vitamin C in blood plasma over 24 hours, as tested against the placebo.
  • the formulation is free of any added stabilizer, and it can be suitably orally administered to the subjects in need thereof, for maintaining significant concentration of vitamin C in blood plasma over prolonged time.

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Abstract

L'invention concerne une formulation stable à libération prolongée de vitamine C, qui est exempte de tout stabilisant ajouté et présente une libération prolongée du principe actif. La formulation est constituée d'au moins un excipient hydrophobe non polymère et d'un agent hydrophile contrôlant la libération conjointement avec au moins un excipient. L'invention concerne également le procédé de préparation, le principe actif pouvant être traité avec un agent hydrophobe contrôlant la libération, suivi d'une granulation aqueuse avec un agent hydrophile contrôlant la libération. Les granules peuvent être convertis en formes posologiques compressibles comme des comprimés ou remplis dans des capsules ou des sachets. La formulation est stable et libère plus de 85 % de vitamine C sur une période de 8 à 24 heures. La formulation peut être administrée par voie orale de manière appropriée aux sujets en ayant besoin, pour maintenir des niveaux efficaces de vitamine C pendant une période prolongée.
EP21909638.5A 2020-12-25 2021-08-24 Formulation stable à libération prolongée de vitamine c et son procédé de préparation Pending EP4267110A1 (fr)

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PCT/IB2021/057747 WO2022136943A1 (fr) 2020-12-25 2021-08-24 Formulation stable à libération prolongée de vitamine c et son procédé de préparation

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US20080248107A1 (en) * 2005-08-24 2008-10-09 Rubicon Research Pvt. Ltd. Controlled Release Formulation
EP2144599B1 (fr) * 2007-03-02 2010-08-04 Farnam Companies, Inc. Granules à libération prolongée utilisant des matières cireuses
CN110917144A (zh) * 2019-11-30 2020-03-27 江苏艾兰得营养品有限公司 一种骨架型维生素c缓释微丸及其制备方法

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